SUMMARY: The American Cancer Society estimates that about 39,230 new cases of primary liver cancer and intrahepatic bile duct cancer will be diagnosed in the US for 2016 and 27,170 patients will die of their disease. Liver cancer is seen more often in men than in women and the incidence has more than tripled since 1980. NEXAVAR® (Sorafenib) was approved by the FDA in 2007 for the treatment of unresectable HepatoCellular Carcinoma (HCC). There are however no proven or approved second line treatment options for patients with advanced HCC. STIVARGA® (Regorafenib) is a small molecule, multikinase inhibitor, that blocks a variety of kinases known to promote angiogenesis (VEGF Receptor Tyrosine Kinases), oncogenesis (c-kit, BRAF, BRAF-V600E) and the tumor microenvironment (PDGFR, FGFR). STIVARGA® demonstrated significant activity as second line treatment in a phase II study, in patients with intermediate or advanced HCC, who had disease progression on NEXAVAR®.
RESORCE (REgorafenib after SORafenib in hepatocellular Carcinoma) is a double-blind, placebo-controlled, multicenter, phase III trial in which 573 patients were randomized in a 2:1 ratio to receive either STIVARGA® (N=379) or placebo (N=194). Enrolled HCC patients had Barcelona Clinic Liver Cancer (BCLC) stage B or C, Child-Pugh A liver function and had received NEXAVAR® for 20 days or more at 400 mg/day or more and had documented radiological progression on NEXAVAR®. Patients received either STIVARGA® 160 mg or placebo once daily during weeks 1-3 of each 4-week cycle. All patients received Best Supportive Care and treatment was continued until disease progression, death, or unacceptable toxicity. The Primary endpoint was Overall Survival (OS) and Secondary endpoints included Progression Free Survival (PFS), Time to Progression (TTP), Response Rate (RR), and Disease Control Rate (DCR).
After a median of 3.6 months of treatment, the OS was 10.6 months for the STIVARGA® group versus 7.8 months for the placebo group (HR=0.62; P<0.001). The median PFS with STIVARGA® versus placebo was 3.1 months vs 1.5 months (HR=0.46; P<0.001) respectively. These findings meant a 38% reduction in the risk of death and a 54% reduction in the risk of progression or death, compared to placebo. When compared with placebo, median TTP with STIVARGA® was 3.2 vs 1.5 months (HR 0.44; P<0.001), DCR defined as complete and partial responses plus stable disease was 65.2% vs 36.1% (P<0.001) and overall RR (Complete and Partial responses) were 10.6% vs 4.1% (P=0.005), respectively. Grade 3 or higher adverse events occurred more frequently with STIVARGA® when compared with placebo and included hypertension, hand-foot syndrome, fatigue and diarrhea.
The authors concluded that STIVARGA® significantly improved OS in patients with HCC who progressed during treatment with NEXAVAR®, pointing out that we have an effective second-line agent for a very difficult-to-treat cancer. Efficacy and safety of regorafenib versus placebo in patients with hepatocellular carcinoma (HCC) progressing on sorafenib: Results of the international, randomized phase 3 RESORCE trial. Bruix J, Merle P, Granito A, et al. Ann Oncol (2016) 27 (suppl 2): ii140-ii141 doi:10.1093/annonc/mdw237.03
